Serendipitous isolation of a disappearing conformational polymorph of succinic acid challenges computational polymorph prediction

A conformational polymorph (γ) of succinic acid was discovered in an attempt to purify a leucine dipeptide by cocrystallization from a methanol solution in the presence of various impurities, such as trifluoroacetic acid. The new γ form was found to have crystallized concomitantly with the most stable β form. In light of this situation, a crystal structure prediction study was undertaken to examine the polymorph landscape. These studies reveal that the γ polymorph is thermodynamically competitive with the other observed polymorphs; having a more stable folded conformation than the planar crystalline conformation in the β form, but being stabilized less by the intermolecular interactions. Simulations and experiment show that the folded conformation is dominant in solution, but that trapping long-lived crystals of the new metastable polymorph may be challenging. Thus the γ polymorph provides a stringent test of theories for predicting which thermodynamically plausible structures may be practically important polymorphs

Structural Motifs in Salts of Sulfathiazole: Implications for Design of Salt Forms in Pharmaceuticals APIs

YesThe creation of salts is a frequently used approach for the modification of physicochemical properties of an active pharmaceutical ingredient. Despite the frequency of application, there has been little research into the structural-property relationships of the final material and the nature of the counterion present. This work reports on five new salts of sulfathiazole and compares the energetics of the intermolecular interactions with variation in the crystal packing motifs

Co-crystals of an agrochemical active – A pyridine-amine synthon for a thioamide group

Five novel co-crystals of thiophanate-ethyl (TE), an agrochemical active, with di(2-pyridyl)ketone (1), 2-benzoylpyridine (2), 3-benzoylpyridine (3), 4-phenylpyridine (4) and biphenyl (5) were found and crystal structures of four of them (TE1–TE3, TE5) solved by single crystal X-ray diffraction. Three of the co-crystals (TE1–TE3) form by way of a reliable pyridine-amine hydrogen bond synthon and one (TE5) because of close packing effects. The fifth co-crystal was identified by X-ray powder diffraction. The work demonstrates the usage of a reliable supramolecular synthon for crystal engineering, while concurrently reminds that the close packing of even very similar molecules cannot be fully predicted.peerReviewe

Folding Patterns in a Family of Oligoamide Foldamers

A series of small, unsymmetrical pyridine-2,6-dicarboxylamide oligoamide foldamers with varying lengths and substituents at the end groups were synthetized to study their conformational properties and folding patterns. The @-type folding pattern resembled the oxyanion-hole motifs of enzymes, but several alternative folding patterns could also be characterized. Computational studies revealed several alternative conformers of nearly equal stability. These folding patterns differed from each other in their intramolecular hydrogen-bonding patterns and aryl-aryl interactions. In the solid state, the foldamers adopted either the globular @-type fold or the more extended S-type conformers, which were very similar to those foldamers obtained computationally. In some cases, the same foldamer molecule could even crystallize into two different folding patterns, thus confirming that the different folding patterns are very close in energy in spite of their completely different shapes. Finally, the best match for the observed NOE interactions in the liquid state was a conformation that matched the computationally characterized helix-type fold

The Impact of Trifluoroacetic Acid on Peptide Cocrystallization: Multicomponent Crystals of l‑Leu‑l‑Leu Dipeptides

In a previous contribution, entitled “First Steps for the Direct Purification of l-Leu-l-Leu Dipeptide through Cocrystallization”, we reported and evidenced cocrystallization as a route to purify freshly synthesized trifluoroacetic acid (TFA)-contaminated Leu-Leu peptides. In this contribution ternary and quaternary crystal forms, isolated as transient phases to the previously reported pure cocrystals, are presented. This contribution and the one previously reported present the outcomes of large cocrystallization screening undertaken on the l-Leu-l-Leu dipeptide, where a competing range of multiple crystal forms from target cocrystal to TFA salt is accessible. As a key point for this contribution we report the isolation of transient phases that consist of Leu-Leu peptide (both with amidic and carboxylic C-terminals) either with pyridazine, 1<i>H</i>-pyrazole, pyridine <i>N</i>-oxide, or pyrazine plus TFA, or solvent alcohol or water with TFA. Such a diversity of multicomponent phases add further to the understanding of the differential crystallization process established when cocrystallization is used to purify the crude synthesized peptide product contaminated with TFA. A description of the overall packing landscape was undertaken from a crystal engineering point of view to illustrate how the presence of trifluoroacetate anions, strong hydrogen bond acceptors, affect the crystal packing. Typically, the Leu-Leu peptide forms a multilayered structure with guest in cavities between the layers; however, alternative novel arrangements were also seen. The structures are part of a wide landscape of possible complexes that are difficult to isolate, as they often represent transient phases that are hard to reproduce. Nevertheless, the reported phases give further insight into the purification through cocrystallization pathway and, critically, help to understand the interplay between crystal growth and the packing landscape

Synthesis of 1,2,4-Triazol-3-imines via Selective Stepwise Cycloaddition of Nitrile Imines with Organo-cyanamides

A convenient method for the synthesis of 1,2,4-triazol-3-imines through a selective, formal, 1,3-dipolar cycloaddition of organo-cyanamide ions with nitrile imine dipoles is reported. Hydrolysis of the 1,2,4-triazol-3-imines yields the corresponding 1,2,4-triazol-5-ones. A stepwise mechanism, supported by DFT calculations, is invoked to explain the reaction selectivity

Multi-component crystals of 4-phenylpyridine: challenging the boundaries between co-crystal and organic salt formation with insight into solid-state proton transfer

Six new multi-component crystals between 4-phenylpyridine and substituted benzoic acids (3-nitrobenzoic acid, 3,5-dinitrobenzoic acid, gallic acid, 4-aminobenozic acid, salicylic acid and 2-aminobenzoic acid) were created and characterized crystallographically to investigate the influence of chemical and structural factors on the hydrogen location between the two components. While the expected intermolecular interactions are formed between the acid and pyridine group in most cases, the gallic acid structure is anomalous forming an unexpected salt with pyridine to hydroxyl interactions. Calculations of the hydrogen bonding motifs indicate that the level of proton transfer (e.g. salt versus co-crystal formation) is not solely a function of the dimer geometry but influenced by the local crystallographic environment. Analysis of the crystal structures indicates the strength of the hydrogen bonding into this motif alters the expected protonation state from chemical considerations